Enterovirus A71 exploits peripheral circulating extracellular vesicles to facilitate blood-brain barrier permeability

Enterovirus A71 infection can cause hand, foot, and mouth disease to occasionally develop the severe neurological complications, but how peripheral Enterovirus A71 infection affects the blood-brain barrier remains incompletely understood. Here, we show that Enterovirus A71 infection of peripheral susceptible cells increases the release of extracellular vesicles and promotes the enrichment of microRNA-30 and microRNA-34 within these vesicles. The extracellular vesicle-associated microRNAs suppress Notch1 signaling in human brain microvascular endothelial cells, impair endothelial junctional integrity, and increase blood-brain barrier permeability.

Activation of Notch1 signaling restores barrier integrity and reduces viral neuroinvasion in neonatal mice. Clinically, serum extracellular vesicle-associated microRNA-30 and microRNA-34 are elevated in patients with severe Enterovirus A71-associated hand, foot, and mouth disease. Together, our findings identify circulating extracellular vesicles as mediators linking peripheral Enterovirus A71 infection to blood-brain barrier dysfunction and suggest that the microRNA-30/34–Notch1 axis contributes to neurological disease progression during severe Enterovirus A71 infection.

We sincerely thank the Biobank of Henan Children’s Hospital. This work was supported by the National Natural Science Foundation of China (No. 32070148 to Z.L., No. 82372229 to Y.J.), the China Postdoctoral Science Foundation (No. 2024T170246 and 2024M750815 to Y.J.), the Open Grant from the Pingyuan Laboratory (No. 2023PY-OP-0202 to Y.J.), the Program for Innovative Talent Development in Higher Education Institutions of Henan Province (No. 25HASTIT055 to Y.J.), and the Outstanding Youth Science Foundation Project of Henan Province (No. 252300421122 to Y.J.). These authors contributed equally: Yicong Liang, Yi Meng, Yue Kong, Shanyu Huang.

Institute of Medical Microbiology, Department of Immunology and Microbiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China Yicong Liang, Yi Meng, Shanyu Huang, Zhaoyang Zhou, Shuang Liu, Xing Zhou & Zhen Luo State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510182, China Department of Microbiology and Immunology, Basic Medicine College, Jinan University, Guangzhou, 510632, China Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA Department of Infectious Diseases, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, 450001, China College of Public Health, Zhengzhou University, Zhengzhou, 450001, China Guangzhou National Laboratory, Bio-Island, Guangzhou, Guangdong, 510005, China Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China Correspondence to Yuefei Jin, Jingyou Yu or Zhen Luo. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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